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The Immunity Puzzle: Why Viruses Like COVID-19 Can Reinfect Hosts, Evade the Immune Response

Researchers from Brigham and Women’s Hospital and Harvard Medical School found that humans tend to produce antibodies that target the same viral regions repeatedly, called “public epitopes.” Using a tool called VirScan, the team analyzed blood samples from the U.S., Peru, and France, and discovered 376 commonly targeted epitopes. These public epitopes allow viruses to mutate a single amino acid and reinfect previously immune populations. The findings have significant implications for understanding immunity, predicting immune responses, and developing therapies and vaccines.

Using a tool called VirScan, Brigham investigators found that people produced shared antibody responses to certain regions of the virusA virus is a tiny infectious agent that is not considered a living organism. It consists of genetic material, either DNA or RNA, that is surrounded by a protein coat called a capsid. Some viruses also have an outer envelope made up of lipids that surrounds the capsid. Viruses can infect a wide range of organisms, including humans, animals, plants, and even bacteria. They rely on host cells to replicate and multiply, hijacking the cell's machinery to make copies of themselves. This process can cause damage to the host cell and lead to various diseases, ranging from mild to severe. Common viral infections include the flu, colds, HIV, and COVID-19. Vaccines and antiviral medications can help prevent and treat viral infections.” data-gt-translate-attributes=”[{“attribute”:”data-cmtooltip”, “format”:”html”}]”>virus, likely leading to selective pressure and new variants that can repeatedly escape detection by prior immunity.

The human body is capable of creating a vast, diverse repertoire of antibodies—the Y-shaped sniffer dogs of the immune system that can find and flag foreign invaders. Despite our ability to create a range of antibodies to target viruses, humans create antibodies that target the same viral regions again and again, according to a new study led by investigators from Brigham and Women’s Hospital, a founding member of the Mass General Brigham healthcare system, and Harvard Medical School. These “public epitopes” mean that the generation of new antibodies is far from random and that a virus may be able to mutate a single amino acidAny substance that when dissolved in water, gives a pH less than 7.0, or donates a hydrogen ion.” data-gt-translate-attributes=”[{“attribute”:”data-cmtooltip”, “format”:”html”}]”>acid to reinfect a population of previously immune hosts. The team’s findings, which have implications for our understanding of immunity and public health, will be published today (April 6) in the journal Science.

“Our research may help explain a lot of the patterns we’ve seen during the COVID-19First identified in 2019 in Wuhan, China, COVID-19, or Coronavirus disease 2019, (which was originally called "2019 novel coronavirus" or 2019-nCoV) is an infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). It has spread globally, resulting in the 2019–22 coronavirus pandemic.” data-gt-translate-attributes=”[{“attribute”:”data-cmtooltip”, “format”:”html”}]”>COVID-19 pandemic, especially in terms of re-infection,” said corresponding author Stephen J. Elledge, PhD, the Gregor Mendel Professor of Genetics at the Brigham and HMS. “Our findings could help inform immune predictions and may change the way people think about immune strategies.”

Alignment of multiple antibodies that use a lysine-specific GRAB motif shows that they recognize their targets in very similar ways. Credit: Stephen J. Elledge, PhD, and Ellen L. Shrock, PhD.

Before the team’s study, there were hints, but no clear evidence, that people’s immune systems didn’t target sites on a viral protein at random. In isolated examples, investigators had seen recurrent antibody responses across individuals—people recreating antibodies to home in on the same viral protein location (known as an epitope). But the study by Elledge and colleagues helps explain the extent and underlying mechanisms of this phenomenon.

The team used a tool the Elledge lab developed in 2015 called VirScan, which can detect thousands of viral epitopes — sites on viruses that antibodies recognize and bind to — and give a snapshot of a person’s immunological history from a single drop of blood. For the new study, the researchers used VirScan to analyze 569 blood samples from participants in the U.S., Peru, and France. They found that recognition of public epitopes — viral regions recurrently targeted by antibodies — was a general feature of the human antibody response. The team mapped 376 of these commonly targeted epitopes, uncovering exactly where antibodies bind their targets. The team found that antibodies recognized public epitopes through germline-encoded amino acid binding (GRAB) motifs—regions of the antibodies that are particularly good at picking out one specific amino acid. So, instead of randomly choosing a target, human antibodies tend to focus on regions where these amino acids<div class="cell text-container large-6 small-order-0 large-order-1">
<div class="text-wrapper"><br />Amino acids are a set of organic compounds used to build proteins. There are about 500 naturally occurring known amino acids, though only 20 appear in the genetic code. Proteins consist of one or more chains of amino acids called polypeptides. The sequence of the amino acid chain causes the polypeptide to fold into a shape that is biologically active. The amino acid sequences of proteins are encoded in the genes. Nine proteinogenic amino acids are called "essential" for humans because they cannot be produced from other compounds by the human body and so must be taken in as food.<br /></div>
</div>” data-gt-translate-attributes=”[{“attribute”:”data-cmtooltip”, “format”:”html”}]”>amino acids
are available for binding, and thus repeatedly bind the same spots.

A small number of mutations can help a virus avoid detection by these shared antibodies, allowing the virus to reinfect populations that were previously immune.

“We find an underlying architecture in the immune system that causes people, no matter where in the world they live, to make essentially the same antibodies that give the virus a very small number of targets to evade in order to reinfect people and continue to expand and further evolve,” said lead author Ellen L. Shrock, PhD, of the Elledge lab.

Interestingly, the team notes that nonhuman speciesA species is a group of living organisms that share a set of common characteristics and are able to breed and produce fertile offspring. The concept of a species is important in biology as it is used to classify and organize the diversity of life. There are different ways to define a species, but the most widely accepted one is the biological species concept, which defines a species as a group of organisms that can interbreed and produce viable offspring in nature. This definition is widely used in evolutionary biology and ecology to identify and classify living organisms.” data-gt-translate-attributes=”[{“attribute”:”data-cmtooltip”, “format”:”html”}]”>species produce antibodies that recognize different public epitopes from those that humans recognize. And, while it is more likely for a person to produce antibodies against a public epitope, some people do produce rarer antibodies, which may more effectively protect them from reinfection. These insights could have important implications for treatments developed against COVID-19, such as monoclonal antibodies, as well as for vaccine design.

“The more unique antibodies may be a lot harder to evade, which is important to consider as we think about the design of better therapies and vaccines,” said Elledge.

Reference: “Germline-encoded amino acid-binding motifs drive immunodominant public antibody responses” by  Shrock EL et al., 6 April 2023, Science.
DOI: 10.1126/science.adc9498
Funding: This research was supported by the SARS-CoV-2Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the official name of the virus strain that causes coronavirus disease (COVID-19). Previous to this name being adopted, it was commonly referred to as the 2019 novel coronavirus (2019-nCoV), the Wuhan coronavirus, or the Wuhan virus.” data-gt-translate-attributes=”[{“attribute”:”data-cmtooltip”, “format”:”html”}]”>SARS-CoV-2 Viral Variants Program and the Value of Vaccine Research Network, the MassCPR, the National Institutes of Health (1P01AI165072, K99DE031016, AI139538, AI169619, AI170715, and AI170580),  the National Science Foundation (Graduate Research Fellows Program), Pemberton-Trinity Fellowship, Sir Henry Wellcome Fellowship (201387/Z/16/Z), Jane Coffin Childs Postdoctoral Fellowship, Burroughs Wellcome Career Award in Medical Sciences. Elledge is an Investigator with the Howard Hughes Medical Institute.

Disclosures: Elledge and co-author Tomasz Kula are founders of TSCAN Therapeutics and ImmuneID. Elledge is a founder of MAZE Therapeutics and Mirimus, and serves on the scientific advisory board of Homology Medicines, TSCAN Therapeutics, MAZE Therapeutics, none of which impact this work. Shrock was a consultant for ImmuneID. Elledge and Kula are inventors on a patent application filed by the Brigham and Women’s Hospital (US20160320406A) that covers the use of the VirScan library to identify pathogen antibodies in blood.

Source: SciTechDaily